Lower plasma magnesium, measured by nuclear magnetic resonance spectroscopy, is associated with increased risk of developing type 2 diabetes mellitus in women: Results from a Dutch prospective cohort study 25 2 Introduction The global prevalence of type 2 diabetes mellitus (T2D) has increased over the past few decades 1, and certain modifiable risk factors, including obesity and insulin resistance as well as inadequate intake of vitamins and minerals, have received considerable interest 2,3. Magnesium (Mg) is an essential cofactor for multiple enzymatic pathways involved in energy metabolism and modulation of insulin-mediated glucose uptake 4 and has been associated with inflammation and endothelial dysfunction 5,6. Not surprisingly, Mg levels have been linked to several cardiovascular diseases, including ischemic heart disease, stroke and hypertension, but also to T2D 7–13. Nearly 99% of the magnesium in the body is found in the bone, muscle and soft tissues 14,15. Only about 0.3-1% is present in serum, with a mean Mg concentration of nearly 0.85 mmol/L. Of this 70-80% is available in the free ionized form and the rest is bound to proteins, phosphate, citrate and other compounds. In current clinical laboratories, Mg is measured largely as total Mg with the predominant techniques being: 1) photometry, which uses a number of chromogenic substances such as xylidyl blue, and 2) atomic absorption spectroscopy 15. Determination of ionized Mg has been problematic and ion-selective electrodes for measuring ionized Mg potentiometrically have historically suffered from a lack of selectivity as well as relatively long response times. In recent years, efforts have been underway to optimize measurement of ionized Mg in plasma and serum due to numerous publications promoting the relevance of ionized Mg in different clinical situations and potential superiority of ionized Mg over total Mg concentrations 15. Recently, a clinical nuclear magnetic resonance spectroscopy (NMR) instrument (Vantera® Clinical Analyzer) was developed that addresses the limiting factors of research NMR instruments and allows for the simultaneous quantification of lipoprotein particles, metabolites and an inflammatory marker in the clinical laboratory 16–19. The aim of the current study was to develop and validate an assay for quantifying ionized Mg in plasma using NMR spectra collected for routine lipoprotein quantification on a clinical laboratory instrument. In this way, Mg can be measured in addition to routine lipoprotein quantification without incurring extra costs. With this newly developed NMR-based assay, we further aimed to determine the prospective association of NMRmeasured Mg and the risk of developing T2D in a large Dutch cohort study.
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